On the Mechanism of Plasma Cholesterol Reduction in the Rat Given Probucol

Abstract

The effects of the cholesterol-lowering drug probucol on lipoprotein metabolism and on the key enzymes that regulate hepatic cholesterol metabolism in the rat were studied. Probucol given for 2 wk was accompanied by a significant reduction in plasma concentrations of low-density and high-density lipoproteins (LDL,HDL). The fractional catabolic rates of the apolipoproteins of HDL and LDL (apoHDL,apoLDL) were not affected by probucol, although the absolute rates of catabolism of both the apolipoproteins were significantly reduced. The activities of 3-hydroxy-3-methylglutaryl CoA reductase and cholesterol 7.alpha.-mono-oxygenase, as well as the rate of hepatic sterol synthesis, were unchanged during the first 2 wk of probucol. More prolonged probucol led to inhibition of the activity of these enzymes and reduction in sterol synthesis, although the liver cellular content of cholesterol significantly increased. A principal mode of action of the drug probably is to reduce the rate of lipoprotein synthesis.